NOVEL SYNERGISTIC THERAPY FOR CYSTIC FIBROSIS

临床诊断为囊性纤维化(CF)和 汗液钠和氯化物浓度的增加会导致慢性和 进行性肺部感染。来自几个属的细菌已经被 分离自CF患者下呼吸道，但P. 铜绿假单胞菌是最常见的。有针对性的抗生素治疗 这种细菌可以改善肺功能。然而，反复的疗程 抗生素治疗与耐药菌株的出现和 药物毒性。大剂量妥布霉素雾化吸入低剂量 慢性阻塞性肺疾病患者呼吸道产生杀菌浓度 化痰，改善肺功能。药物毒性检测不到 而且耐药菌的出现频率并没有增加。 需要大剂量的妥布霉素，因为痰中有拮抗作用 妥布霉素通过与抗生素的DNA结合和通过 它的二价阳离子含量很高。我们发现，前处理对 含有重组人DNA酶(Rh DNase)的痰可缓解大部分 妥布霉素活性的拮抗作用。自喷雾给药以来 RhDNase通过降低痰黏度改善肺功能(和 通过推断，增加粘液-纤毛清除)，我们假设 雾化吸入重组人脱氧核糖核酸酶和妥布霉素改善了CF患者的病情 肺功能比单独使用任何一种药物都要好。为了检验这一假设，我们 将：1)确定妥布霉素的最低杀菌浓度 在DNA酶处理过的30株铜绿假单胞菌的痰中，2)设计了一种 允许妥布霉素和妥布霉素联合给药的气雾剂给药系统 RHDNase，3)进行试点研究，以验证交付的充分性 系统，两种制剂在痰中的药代动力学及其对患者的影响 和4)进行多中心、双面罩、 每种药物的随机、安慰剂对照的平行研究 联合检测FEV1和痰细菌密度。这种疗法有 延长CF患者生命的机会，直到纠正 基本缺陷是可行的。

Individuals with a clinical diagnosis of cystic fibrosis (CF) and increased sweat sodium and chloride concentration suffer from chronic and progressive pulmonary infection. Bacteria from several genera have been isolated from the lower respiratory tract of CF patients, but P. aeruginosa are the most prevalent. Antibiotic therapy directed against this bacterium improves pulmonary function. However, repeated courses of antibiotic therapy are associated with emergence of resistant strains and drug toxicity. Aerosolization of high doses of tobramycin into the lower respiratory tract of CF patients produces bactericidal concentrations in sputum and improves pulmonary function. Drug toxicity is not detectable and the frequency of emergence of resistant bacteria is not increased. High doses of tobramycin are required because sputum antagonizes tobramycin bioactivity through DNA binding of the antibiotic and through its high content of divalent cations. We have found that pretreatment of sputum with recombinant human DNase (rhDNase) mitigates much of the antagonism of tobramycin activity. Since aerosol administration of rhDNase improves pulmonary function by decreasing sputum viscosity (and by inference, increasing muco-ciliary clearance), we hypothesize that "aerosol administration of rhDNase and tobramycin to CF patients improves pulmonary function than either agent alone". To test this hypothesis we will: 1) determine the minimal bactericidal concentration of tobramycin in DNase treated sputum for 30 P. aeruginosa isolates 2) devise an aerosol delivery system permitting coadministration of tobramycin and rhDNase, 3) conduct a pilot study to verify adequacy of the delivery system, the sputum pharmacokinetics of both agents and their effect on pulmonary ventilation, and 4) conduct a multicenter, double-masked, randomized, placebo-controlled parallel study of each agent alone and in combination on FEV1 and sputum bacterial density. This therapy has the opportunity to prolong the life of CF patients until correction of the basic defect is feasible.